N-substituted amides of natural fatty acids

ABSTRACT

Novel N- Alpha -(C1-C4)alkyl-benzyl natural fatty acid amides of the formula   WHEREIN R1 is a fatty acid residue of a naturally occurring oil such as safflower oil etc., and R2 is alkyl of 1-4 carbon atoms having excellent blood cholesterol lowering effects are provided.

United States Patent 1 1 1 1 3,741,999 14 1 June 26, 1973 Seki 'et al.

N-SUBSTITUTED AMIDES OF NATURAL FATTY ACIDS I Inventors: Takashi Seki,Toyonaka;,Katsuyuki I (Told, Nishinomiya; Hiroshi Nakatani, Toyonaka;Yoshlo Suzuki, Amagasaki; Hideaki Fukushima, Takatsuki; YoshioNawasltiro,

Moriguchi, all of Japan Assignee: Sumitomq Cliemicaltlm, Lt'rL,

Higashi-ku, Qsaigaalapan; Filed: 'se 1.10,1 97o-.

Appl. No.: 71,205"

Related US. Application Data Continuation-impart of Ser. No. 450,534,April 23,

1965, Pat. No. 3,551,462. I

Foreign Application Priority, Data Field of Search 260/404; 424/320,

[56] R rer nees Cited I UNITED STATES PATENTS 3,193,458 7/1965 Shapiroet a1 424/320 2,978,381 4/1961 Freedman et al 424/106 OTHER PUBLICATIONSAndre et al., d-Ricinoleates of a-phenethylamine V 7 etc); (1932) CA 26pp. 2702-2703 (1932). Hashim et al., Effect of Mixed Fat Formula Feedingetc.; (1959) CA53 p. 7338 (1959).

I Primary Examiner-Lewis Gotts Assistant Examiner-G. l-lollrahAttorney-Wenderoth, Lind and Ponack [571 ABSTRACT Novel Nea-(C-Coalkyl-benzyl natural fatty acid amides of the formula wherein R is afatty acid residue of a naturally occurring oil such as saffloweroiletc., and R is alkyl of 1-4 carbon atoms having excellent bloodcholesterol lowering effects are provided.

5 Claims, No Drauiings This application is a continuation-in-part ofSer. No. 450,534, filed Apr. 23, 3,551,462.

This invention relates to novel anti-atherosclerosis agents. Moreparticularly, the invention pertains to novel N-substituted naturalfatty acid amide derivatives which are useful for lowering the elevatedlevels of cholesterol or lipids.

Atherosclerosis is an adult disease for which there is no knownsatisfactory cure. Although the cause for atherosclerosis is not yetknown in spite of discussions in the academic circles, it has broadlybeen recognized that one of the most significant histo-pathologicalmanifestations of atherosclerosis is the deposition of cholesterol orlipids in the blood. v

A number of experimental and clinical facts have been reported, whichindicate that the reduction of the elevated blood cholesterol or lipidlevel is considered extremely important for the prevention ofatherosclerosis.

The present inventors have found a group of novel compounds which areeffective as cholesterol-lowering agents and which are substantiallynon-toxic.

An object of the presentinvention is to provide N- substituted naturalfatty acid amide derivatives usable as anti-atherosclerosis agentshaving prominent effects and extremely high-admissibility.

Other objects and merits of the invention will be apparent from thefollowing description.

In order to accomplish these objects, the present invention providesnovel N-a-alkyl-benzyl natural fatty acid amides of the formula whereinR is a fatty acid residue ofa naturally occurring oil, said fatty acidhaving an iodine value of at least 50, and R is C -C alkyl, providedthat in case the oil is sesame oil, safflower oil, soybean oil orcuttlefish oil, R is C -C, alkyl.

The phrase fatty acid residue of a naturally occurring oil refers tofatty acid residues of fatty acids which are present in naturallyoccurring oils. Examples of the naturally occurring oils includevegetable oils, animal oils, etc., such as sesame oil, safflower oil,cuttlefish oil, linseed oil, soybean oil, sunflower oil, corn oil,cottonseed oil, olive oil, peanut oil, flatfish oil, sardine oil, codoil, menhaden oil, whale oil, residual oil (liver oil from which vitaminA has been removed), perilla oil and menuke oil, the preferred examplesbeing safflower oil, linseed oil, soybean oil, corn oil, cottonseed oil,sunflower oil, cuttlefish and sardine oil.

The processes for the production of the N-substituted natural fatty acidamides of the present inventon natu rally vary, for example, dependingupon the nature of R, and R and the origin of the acid moiety of theamfatty acid is reacted 1965, now US. Pat. No. 5

ides. Owing to their great number it is not possible tqi,

describe all of them in detail, which is in any case un-- necessarysince they are all based on conventional or ganic chemistry processes.However, details of typical.

and suitable processes are given below.

A natural oil is hydrolyzed and the resultant natural directly with anamine of the formula (R is as defined before) in the presence ofadehydrating agent such as a disubstituted carbodiimide compound, in anaqueous or organic solvent.

Typical examples of disubstituted carbodiimide compounds are as follows:dialkylcarbodiimides such as diisopropylcarbodiimide and the like:dicycloalkyl carbodiimides such as dicyclohexylcarbodiimides and thelike; and diaryl carbodiimides such as diphenylcarbodiimides,dibenzylcarbodiimides and the like. Of course, carbodiimides other thanthose specifically mentioned can be employed without any trouble.

The condensation reaction between a hydrolyzed natural oil and an amineusing a carbodiimide proceeds smoothly at room temperature, but when thereaction is vigorously exothermic, if necessary, it may be allowed tocool.

Water and substantially all organic solvents can be employed as solvent.Examples of organic solvents are as follows: ethers such as diethylether, tetrahydrofuran and dioxane; esters such as methyl acetate, ethylacetate, and butyl acetate; ketones such as acetone, methyl ethyl ketoneand methyl isobutyl ketone; halogeno alkanes such as chloroform, carbontetrachloride and ethylene dichloride; and hydrocarbon solvents such ascyclohexane, n-hexane, petroleum ether', gasoline, benzene and toluene.They are employed alone or in the formv of a mixture thereof in optionalproportions.

The reaction procedure is as follows:

The natural fatty acid, the amine and the disubstituted carbodiimidecompound, at least one of which is dissolved in a solvent, are mixed atroom temperature or under cooling, if required, and the mixture isallowed to stand for 3 to 24 hours while being stirred as necessary. Tothe reaction mixture is added a small portion of acetic acid todecompose theexcess carbodiimide and the urea derivative formed isfiltered off to yield the fatty acid amide in the filtrate.

Alternatively, a natural oil is reacted with an amine of the aforesaidformula. That is, about l mol. of the oil and l to equivalent mols ofthe amine are mixed in the absence or presence of solvents, e.g.alcohols such as methanol, ethanol or the like, aromatic hydrocarbonessuch as benzene, toluene, xylene or the like, halogenoalk-anes such asmethylenechloride, chloroform, carbon tetrachlorideor the like, alkenesor alkanes such as petroleum ether, benzine, gasoline, ligroin orcyclohexane, and ethers such as tetrahydrofuran, dioxane and the like,or a mixture thereof, and the mixture is subjected to reaction in theabsence or presence of a catalytic amount, or equimolar amount to theamine, or. an auxiliary condensation agent, such as an alcoholate oranalkali metal, i.e. lithium methylate, lithium ethylate, sodiummethylate, sodium ethylate, potassium-t-butylate and the like, or acidicauxili rx agents, i.e. p-to'lue'nes'ulfonic acid and the like, to

yield. the amide derivatives. In this reaction, the alcohol formed maybe removed from the reaction system.

It is a matter of course that the reaction will proceed I: :ggjggfg'ggeven in the absence of solvents and auxiliary agents. 4 3 199.2 3/0:o5In case of using amines having a lower boiling point, 2 1: ggg-gigg-g:if necessary, an autoclave may be employed, but in case 7 "mo", 5 1going/:04 of other amines the reaction mixture is stirred under 8 I 1-01", b l 2l atmospheric pressure while being heated as necessary, g{gijfijgfij thereby easily yielding the objective amide. 11 J i-Cfl-l. b199-212/0..o4 In carrying out the reaction. the mixture of reactants bzos'nolo'os l3 Cuttlefish Oll C,H, a 200209/0.05 1s strrred at asuitable temperature of between room 14 a woq g opy temperature and 400Cfor about 3 hours to a month. lO :2 I: '93 {33-5} 8-8; If necessary, thereaction is carried on in an atmol7 u Z in sphere of an inactive gassuch as nitrogen, helium and l8 -61". a 2004221005 the like to preventproduction of undesirable by- 53 ""U ml igfifijg'gf I products andcolormg, to yield the ob ective product, 21 'n-C lh a 200-210/0.o4 whichcan be subjected to a fractional distillation and 15 I: -2 3 Z 32%: Z88:recrystallization method using a petroleum hydrocare 24 1 igh a19s-2|4/o. o4 bon, acetone or the like, or the urea method, to remove 5g t"- 201424/0-03 saturated fatty acid amides. lf alkali alcoholate isused is 'r. 5833:3823; as an auxiliary a ent, conju ated double bondisomers 2'8 i-CJI, b 19a-219/o.o2

8 8 .1 are partially obtamed. However, the present inventors 20 i3 'g'n'g ggigyg'gi confirmed that saturated andisomerized fatty acid am- 31min: b 205-22510105 ides cause no undesirable effect on the human body.I ff" g lgg'g flg-gg The process for the production of the amides of the4 u 1 g g i g 1nvent1on 1s descnbed 1n more detail wrth reference to 35I n rb 2l -05 the following examples, which are however to be conis vgxgmggg .strued for the purpose of illustration only and not as 38 t-CJLb 200-22l/0.05= 39 corn. oil cl-r. b 200-21 110.03 l1m1t1ng themventron. 4Q b imam/Q05. 41- n-clll, b 202-21s/o. 03 EXAMPLES l-l22 I s2o0 -213/0.0s 43 a n-C 11 b 200-2l4/0.06 General procedure I 4 1 min: b201-2l4/0.05 a. A natural 01] 1s hydrolyzed 1n 1N solut1on of so- 45 v yt-Cr b /0.05 dium hydroxide in methanol and the resulting natural is f yg fggjtggfig fatty acid is treated with urea and methanol to remove 4sn-cnt, b 192-299/aos the saturated fatty. acid. :3 I: g 1 :ggjt lgggggTen grams of the thus obtained natural fatty acid, an 3 5| a bwaltz/0106 a-a lkylbenzylamme and d1cyclohexylcarbod11m1de are. I t-tgtb g l -5538.8: dissolved in benzene and the mixture is allowed to 54 2 31 1 stand overnight at room temperature. Acetic acid. is 55 v n -C:1H1 IM-20410.03. added thereto to decompose the excess amount oldicyis :gn"ggg'gfijg'gg 01 1 1 1 I I, 1 clohex-ylcarbodumrde and the m1xture 1sfiltered to sep- V 58 i-c u. a 20492141003 arate off the decomposedproduct. Then the filtrate is. 23 1 62" fig'ggzg'gg I nu I washedsuccessively w1th5 percent hydrochlorrc ac d, 61 pg g Z [grams/(m5vv 5percent sod1um carbonate aqueous, solution and wag5 -g:|=it a:gg-ggglggg.

. I ia ter, and dried over anhydrous sodium. sulfate Upon 4 u i 893,408,005 evaporanon of the solvent, the. residue 15 d1st1lled 1n; 65.i-CJ'I, a l922,09/0.06

66. t-C 1-1 a; 1994191005 vacuo to y1eld N (1 alkylbenzyl natural 01]fatty acid 67 flamh 0 6 by mums/0.02 am1de. I 68. cm. b 185-208/003 b. Anatural c1]: and an a-alkylbenzylamine are mixed g3 I: 2 Pigs 8'8; andstirred in an atmosphere of nitrogen ata tempera- 71 1. 3 b g a t tureof 135C to 140C for 40 hours. Then the reaction 5 1 i-CJ'I. b1s9-2;l6/0.03 mixtureis distilled in vacuo to yield Ni-a-alltylbenzylsardine 6 62" 8 igg'ggg'gg 1 1 1 il r natural o1l fatty ac1d'am1de. 7sC,H, b 1s4,-21s/o.o3 According to one of the procedures mentioned I: g n:ggfgigjg-gi above, the following ljl-a-alkylbenzyl natural oil fatty 7gI 'I b hi acrd amrdes are obtamed as shown In the followrn 79 t t. bl88-220/0-03 8 Table l 80 C4H11 b l94-225/0.06 I g; cod on (cal89-220/0104 ,7, l88-2l8/0.03 TABLE 1 as can, b 190 2 10/0.oa

34 b l88-2l2/0.05 60 :2 Il-CJ'l b 192-21.4/0.o5 I i-CJ-h, b 195-2 1610.06 117 t-CJ'I, b- 2034261005; 1t,-(;0-N11--C11- as menhaden oil x cma l89-2l9/0.06 s9 cm. a l88-220/0.05 R1 r 90 can, a 1s9 221/0.os g; 1cm, a, 1s9-221/o.0s -C1 1 a 192-222/0.o4 .93 i-cl-l a 192'-220/0.04'Example RI-CO- R2 Pro- BoilingPojnt 94 t-cili: a l98-224/0.04 No.(natural oil) cedure (C/mmHg) 95 whale-oil CH, 21. vl93--2l8/(1.05 i 96Cm, a 19o-221/o.06 I sesame oil C 2H5 21 200-2 l0/0.05- 97 n-C fl, a l92-2l 810.05

98 i-c ll; 'a 194-215/(104 99 n-ciHu a l992l8/0.04 100 i-C H a 200-2 l/0.03 101 t-CJHSI a 202-226/0.06 102 residual oil CH b 194-2 1 7/0.04103 C2: b 192-220/0.03 104 n-CaH: b 194Zl7/0.04 105 iC:iH1 bl93-220/0.05 106 n-C4Ho b l97-222/0.05 107 i'CJH b l99-223/0.06 108l-C4Hu b 200226/0.05 109 perilla oil C H l92208/0.05 1 l0 C H; a190-210/0.05 1 ll n-C H a 190-21 1/0.05 1 12 i-C; H1 a 190213/0.06 113n-CJ-i a 195215/0.05 1 14 i-CJ'ls a 1962l6/0.06 115 t-C H a 200-2 18/002 1 l6 menuke oil CH 8 l842l5/0.06 117 C 11, a 185-2 1 7/007 118 n-CH a 188-218/0.05 1 l9 i-C I-L- a 183-205/0.06 120 1'1'C4Hg a 190-211/0.05 121 i-C H a l91-2l2/0.06 122 l-CJ-i a 200222/0.03

As mentioned above, the N-a-alkylbenzyl natural fatty acid amides of thepresent invention have excellentcholesterol lowering effects. Theeffectiveness of the present amides are set forth-as shown in thefollowing test examples.

TEST EXAMPLES ll 22 Cholesterol Lowering Effects on Mice Mice were fedon a special diet which was supplemented with cholesterol and bileacids. Blood cholesterol level of the mice had been elevated to 3 to 6times the normal level. Each amide compound was well mixed to thespecifical diet in 1 percent administration and fed orally to the micefor 10 days. At each dose level, 10 or 20 mice were used and serum totalcholesterol levels of the blood serum were measured at the end of theexperimental period. One group of mice, in

each set of experiment, was given the specifical diet without the testcompound and served as control. Mean level of serum total cholesterol ofthe treated group was expressed as a per cent of that of the controlgroup (blood cholesterol index).

Results are shown in the following Table 2.

Test R,-CO- R Blood Cholesterol Example No. (natural oil) index (71)Control (no drug) 1 100 linoleic acid 75-80 I sesame oil (I -H 40 2 n-C;H 38 3 i-C H; 34 4 n-C H 33 5 i-C H 37 6 t t-C H. 33 7 safflower oil C11,, 38 8 n-C -,H,- 34 9 i-C -,H,- 35 10 n-C H, 36 l l i-C H 35 12 t-C H34 I3 cuttlefish oil C H, 41 14 n-C;,H 33 I5 i-C H 34 I6 n-C H. 38 17i-C H 39 linseed oil oil oil

1 l5 t-C,H, 38 H6 menuke oil CH, 38 1 17 c, 40 l 18 n-C,H, 32' 119i-C,H, 39 120 n-CJ-l, 38 121 i-CJ-l, 39 122 t-C,H, as

The extremely low toxicities of the instant amides are also an aspect ofthe present invention.

The cholesterol-lowering agent in this invention may be orallyadministered. Usually the amount orally administered is 0.1 g. 20 g. perday for a human adult, preferably 0.5 g. 5 g. per day, and theadministration may be continued for l-5 months, usually for about 3months. For example, the amide can be orally administered to a humanadult in an amount of 2.0 g. per day for about 3 months. Thecholesterol-lowering agent may be employed in any suitable form which isconventional for oral administration. Thus, it may be encased in acapsule, in liquid form, in tabletform, or in powder form. In preparingthe agents in these various forms, the active compound may be used assuch, without being mixed with a carrier, or mixed with or impregnatedin a suitable solid carrier, or it may be mixed with a liquid carriersuch as an edible oil, preferably those containing linoleic acid. It isalso possible to use a mixture of two or more of the acid amides of theinvention. It may also be used as mixed with linoleic acid.

The content of the acid amide of the composition varies depending uponthe kind of carrier used, and the content is adjusted so that the amideis administered to a patient within the indicated dosage range.

What is claimed is:

l. A compound of the formula wherein R, is a fatty acid residue of anaturally occurring oil selected from the group consisting of sesameoil, safflower oil, cuttlefish oil, linseed oil, soybean oil, sunfloweroil, corn oil, cottonseed oil, olive oil, peanut oil, flatfish oil,sardine oil, cod oil, menhaden oil, whale oil, residual oil, perilla oiland menuke oil, and

R, is an alkyl group containing l-4 carbon atoms, with the proviso thatwhen R, is a fatty acid residue of sesame oil, safflower oil, soybeanoil or cuttlefish oil, R, is an alkyl group containing 2-4 carbon atoms.2. A compound according to claim 1, wherein R, is a fatty acid residueof safflower oil, linseed oil, soybean oil, cuttlefish oil or sardineoil.

3. A compound according to claim 1', wherein R, is a fatty acid residueof linseed oil, sunflower oil, corn oil, cottonseed oil, olive oil,peanut oil, flatfish oil, sardine oil, cod oil, menhaden oil, whale oil,residual oil, perilla oil or menuke oil, and R, is methyl.

4. A compound according to claim 1, wherein R, is a fatty acid residueof sesame oil, safflower oil, soybean oil or cuttlefish oil and R, isalkyl of 2-4 carbon atoms. 5. A compound according to claim 1, wherein Ris a fatty acid residue of safflower oil and R, is alkyl of 2-4 carbonatoms.

1 i II t i

2. A compound according to claim 1, wherein R1 is a fatty acid residueof safflower oil, linseed oil, soybean oil, cuttlefish oil or sardineoil.
 3. A compound according to claim 1, wherein R1 is a fatty acidresidue of linseed oil, sunflower oil, corn oil, cottonseed oil, oliveoil, peanut oil, flatfish oil, sardine oil, cod oil, menhaden oil, whaleoil, residual oil, perilla oil or menuke oil, and R2 is methyl.
 4. Acompound according to claim 1, wherein R1 is a fatty acid residue ofsesame oil, safflower oil, soybean oil or cuttlefish oil and R2 is alkylof 2-4 carbon atoms.
 5. A compound according to claim 1, wherein R1 is afatty acid residue of safflower oil and R2 is alkyl of 2-4 carbon atoms.